Treatment of HIV infection with highly active antiretroviral therapy (HAART) has been of great benefit to patients with HIV disease. Unfortunately it is also associated with a considerable degree of side effects. Among the unanswered questions in the treatment of patients with HIV are the questions of the best time to start therapy and whether or not therapy needs to be life ?long once it is started. To determine whether or not levels of HIV would remain suppressed in the absence of drug following effective therapy a study was carried out in which patients with long-term effective suppression of viral replication had their therapy stopped. Unfortunately, all patients showed a rapid recurrence of viral replication. The lowest levels of viral rebound were in those patients in whom therapy had been started relatively soon following primary HIV infection. The increases in viral replication that were observed following the discontinuation of therapy were associated with decreases in the levels of CD4+ T lymphocytes and increases in the rate of CD4+ T cell turnover. In addition, careful analysis of patients with ongoing high levels of HIV replication in the presence of HAART was able to identify a unique mutation involving the deletion of amino acid 67 of the HIV reverse transcriptase of HIV. The deletion in combination with a T69G mutation led to high level nucleoside resistance without compromise of the ability of the AIDS virus to replicate. An early observation in studies of the immune systems of patients with HIV infection was that these patients had a profound defect in the ability of their peripheral blood mononuclear cells to respond to stimulation with remote recall antigens such as tetanus toxoid. These studies suggested that the CD4 declines seen in the setting of progressive HIV infection were associated with a progressive skewing of the T cell receptor (TCR). This degree of TCR skewing in the setting of a marked decrease in the overall size of the CD4 T cell pool suggests that some elements of the T cell repertoire may be permanently lost in the absence of significant amounts of stem cell differentiation. To determine whether or not the increases in the CD4 T cell pool seen in the context of antiretroviral therapy represents a complete or only partial restoration of the immune system, a study was undertaken in which patients with varying degrees of CD4 T cell recovery were immunized with the neoantigen bacteriophage PhiX174. Immune responses to the neoantigen were significantly less in the patients with treated HIV infection compared to healthy controls. These data suggest that the earlier finding of lack of antigen-specific responses in patients with HIV infection are most likely due to a decrease in the number of antigen-specific clones below a certain critical level.